Human Immunodeficiency Virus-1 (HIV-1) infection has been reported throughout the world in both developed and developing countries. HIV-2 infection is found predominately in West Africa, Portugal, and Brazil. At the end of 2008, an estimated 1,178,350 persons aged 13 and older were living with HIV infection in the United States. Of those, 20% had undiagnosed HIV infections (CDC, “HIV Surveillance—United States, 1981-2008,” MMWR 60(21); 689-693 (2008), which is hereby incorporated by reference in its entirety).
The HIV viruses are members of the Retroviridae family and, more particularly, are classified within the Lentivirinae subfamily. Like nearly all other viruses, the replication cycles of members of the Retroviridae family, commonly known as the retroviruses, include attachment to specific cell receptors, entry into cells, synthesis of proteins and nucleic acids, assembly of progeny virus particles (virions), and release of progeny viruses from the cells. A unique aspect of retrovirus replication is the conversion of the single-stranded RNA genome into a double-stranded DNA molecule that must integrate into the genome of the host cell prior to the synthesis of viral proteins and nucleic acids.
HIV encodes a number of genes including three structural genes—gag, pol, and env—that are common to all retroviruses. The envelope protein of HIV-1 is a glycoprotein of about 160 kd (gp160). During virus infection of the host cell, gp160 is cleaved by host cell proteases to form gp120 and the integral membrane protein, gp41. The gp41 portion is anchored in the membrane bilayer of virion, while the gp120 segment protrudes into the surrounding environment. gp120 and gp41 are more covalently associated, and free gp120 can be released from the surface of virions and infected cells. The gp120 polypeptide is also instrumental in mediating entry into the host cell.
Historically, viral vaccines have been enormously successful in the prevention of infection by a particular virus. Therefore, when HIV was first isolated, there was a great amount of optimism that an HIV vaccine would be developed quickly. However, this optimism quickly faded, because a number of unforeseen problems emerged.
It is widely thought that a successful vaccine should be able to induce a strong, broadly neutralizing antibody response against diverse HIV-1. Neutralizing antibodies, by attaching to the incoming virions, can reduce or even prevent their infectivity for target cells and prevent the cell-to-cell spread of virus in tissue. Conventional wisdom suggests that “constant” rather than “variable” regions of Env would induce the most broadly reactive antibodies. The failure of the Vaxgen HIV vaccine trial demonstrated that the sequence-conserved regions of HIV gp120 do not induce protective neutralizing antibodies, since these regions were present in the gp120 immunogen used in that study. The failure of the STEPS HIV vaccine demonstrated that cellular immunity utilizing non-Env determinants is not protective. Thus, one could conclude that targeting the sequence-conserved (including non-Env and the core of Env) regions of the HIV-1 virus for protective immunity will not work. Thus, there remains a need for envelope antigens that can elicit an immunological response in a subject against multiple HIV strains and subtypes, for example when administered as a vaccine.
The present invention is directed to overcoming deficiencies of prior approaches to addressing HIV infection.